Activins are abundantly expressed in gonads and elicit important autocrine/paracrine actions within the pituitary and hypothalamus. Activins signal through two types of receptors, activin receptor II (ACVR2) and IIB (ACVR2B). ACVR2 is highly conserved evolutionarily and is the predominant form in pituitary gonadotropes. Our genetic studies demonstrated that ACVR2 signaling is important for FSH homeostasis in pituitary, since Acvr2 null mice have suppressed levels of FSH synthesis and secretion. Despite this knowledge, many activin-responsive genes in the reproductive axis remain unknown. Our long-term research goal is to elucidate the in vivo mechanisms of activin signaling pathways that ultimately regulate FSH synthesis and secretion. The central hypothesis is that several critical known/unknown genes downstream of the ACVR2 signaling pathway must be affected in gonadotropes of Acvr2 mutant mice. This hypothesis will be tested in two Specific Aims. In Specific Aim 1, we will use a novel transgenic mouse strain, in which the gonadotropes are labeled with GFP. These mice will be intercrossed to Acvr2 null mice and gonadotropes purified by flow sorting based on GFP fluorescence. This approach will provide pure populations of gonadotropes that have never been exposed to ACVR2 signaling in vivo, at desired time points. In Specific Aim 2, microarray analyses will be performed using gonadotrope RNA samples isolated from control and Acvr2 null mice that express the GFP transgene. These studies should provide new knowledge on activin signaling pathways in gonadotropes and identify novel candidate genes/proteins that are important for FSH synthesis and secretion. Delineation of mechanisms of FSH production is fundamental to physiology of reproduction and offers long-term clinical benefits of diagnosing and treating FSH-dependent fertility/infertility disorders. Finally, because activins regulate multiple processes throughout the reproductive axis and other parts of the body, results obtained from the proposed studies should also provide new mechanistic insights into activin-regulated signaling pathways in other tissues. PROJECT NARRATIVE: These studies should provide new knowledge on how pituitary gland synthesizes and secretes an important hormone called follicle-stimulating hormone (FSH) in response to another locally produced protein called activin. Delineation of mechanisms of FSH production is fundamental to physiology of reproduction and offers clinical benefits of diagnosing and treating FSH-dependent fertility/infertility disorders. These include ovarian hyperstimulation syndrome, amenorrhea and testicular defects.